1. Field of the Invention
The novel compositions of the present invention possess the advantageous pharmacological properties of the known free base compound and in addition have unexpectedly high water-solubility, thus allowing preparation of useful dosage forms for intravenous administration
2. Description of the Prior Art
The acridine derivative m-AMSA [4'9-(acridinylamino)methanesulfon-m-anisidide] has been reported by Cain, et al. in Europ. J. Cancer 10:539-549 (1974) to possess significant antitumor activity in animal tumor systems.
When an antitumor agent such as m-AMSA is employed for pharmaceutical use, it is recognized that solubility of the agent is often the controlling factor in determining route of administration and dosage forms. For instance, a water-soluble substance can be generally administered intravenously whereas a water-insoluble material is limited to other forms of parenteral administration such as intramuscular and subcutaneous. A therapeutic agent having water solubility also facilitates preparation of oral and non-intravenous parenteral dosage forms. Thus, it is decidedly advantageous if a therapeutic agent is water-soluble, particularly when one considers that the most direct route for achieving therapeutic blood levels of a drug is by intravenous administration.
The free-base form of m-AMSA has very limited solubility in water and thus cannot be used as a dosage form for intravenous administration. Attempts have been made to prepare acid addition salts to overcome this solubility problem, but the reported monohydrochloride and monomethanesulfonate salts also proved insufficiently water-soluble.
The m-AMSA formulation presently in clinical use consists of two sterile liquids combined just prior to use. A solution of m-AMSA in anhydrous N,N-dimethylacetamide is contained in an ampule. A separate vial contains an aqueous L(+)-lactic acid solution for use as a diluent. When mixed, the resulting m-AMSA solution is administered by i.v. infusion.
While the present clinical formulation provides an intravenous dosage form, it suffers from several disadvantages. In addition to the obvious difficulties in preparing and administering the dosage form, it contains dimethylacetamide as a vehicle. Dimethylacetamide has been reported to show various toxic symptoms in animals and may thus prove to be unacceptable or undesirale as a pharmaceutical vehicle.
It is accordingly an object of the present invention to provide water-soluble, stable, therapeutically acceptable forms of m-AMSA which can be administered intravenously (as well as by other routes) and which do not contain or require dimethylacetamide as a pharmaceutical vehicle. This object as well as other features and advantages of the invention will be readily apparent to those skilled in the art from the disclosure set out below.
The pyroglutamic acid (L and D,L-2-pyrrolidinone-5-carboxylic acid) used in admixture with the salts of the present invention or as a component of the compositions of the present invention has been reported in U.S. Pat. No. 3,920,814 to potentiate the instrinsic activity and blood levels of certain antibiotics such as penicillin G, penicillin V, ampicillin, cephalothin, gentamycin, tetracycline, etc. That patent also notes that pyroglutamic acid has been reported useful as a medicament for its good psychonormalizing, psychotonic, mood elevating and antitoxic action. Various other patent and literature references disclose pyroglutamate salts including, for example, Boll.Chim. Farm 116 (12): 735-743, 1977 (D,L-pyroglutamate salt of L(+)-arginine), Arzneim.Forsch. 27(8): 1553-1557, 1977 (D,L-pyroglutamate salt of L(+)-arginine), Japanese Published Patent Application No. 50/135,212 (D,L-2-pyrrolidinone-5-carboxylic acid triethanolamine salt as a component in pruritis treatment ointment), Japanese Patent No. 74/27,643 (triethanolammonium D,L-pyroglutamate as an ingredient in shampoo composition), U.S. Pat. No. 3,899,585 (pyroglutamic acid salts of amino acid higher alkyl esters as fungicidal and bactericidal agents; see also U.S. Pat. No. 3,821,403), U.S. Pat. No. 3,947,589 (pyroglutamic acid salts of N-higher aliphatic acyl amino acids for use as fungicidal compositions), Japanese patent No. 74/14,630 (D,L-pyroglutamic acid salts of amino acid alkyl esters for use as fungicides), U.K. Pat. No. 1,352,420 (discloses N-cocoyl-L(+)-arginine ethyl ester D,L-2-pyrrolidinone carboxylate as an antimicrobial or germicidal agent; see also West German Published Patent Application No. 2,131,404, Japanese Patent No. 76/22,055, Japanese Patent No. 76/5413, Oyo Yakuri 11 (6):945-953, 1976, Yukagaku 25 (7): 404-408, 1976, Mem. Tokyo Univ. Agric 20, 51-73, 1978, Japanese Patent No. 78/118,516 and Nippon Nogei Kagaku Kaishi 52 (3): 117-121, 1978.